Diphenhydramine

Diphenhydramine
Diphenhydramine
Systematic (IUPAC) name
2-(diphenylmethoxy)-N,N-dimethylethanamine
Clinical data
Trade names Benadryl
AHFS/Drugs.com monograph
MedlinePlus a682539
Pregnancy cat. A(AU) B(US)
Legal status Over-the-counter
Routes Oral, parenteral (IM), parenteral (IV), topical, suppository
Pharmacokinetic data
Bioavailability 86% bound to plasma protein
Protein binding 98 to 99%
Metabolism Various cytochrome P450 liver enzymes: CYP2D6 (80%), 3A4 (10%)[1]
Half-life 2.4-9.3 hours[2]
Excretion 94% through the urine, 6% through feces [3]
Identifiers
CAS number 58-73-1 YesY
ATC code D04AA32 D04AA33, R06AA02
PubChem CID 3100
IUPHAR ligand 1224
DrugBank DB01075
ChemSpider 2989 YesY
UNII 8GTS82S83M YesY
KEGG D00669 N
ChEBI CHEBI:4636 YesY
ChEMBL CHEMBL1620 N
Chemical data
Formula C17H21NO 
Mol. mass 255.355 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Diphenhydramine hydrochloride (play /ˌdaɪfɛnˈhaɪdrəmiːn/; abbreviated DPH, sometimes DHM) is a first-generation antihistamine mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason is often used as a nonprescription sleep aid and a mild anxiolytic. The drug also acts as an antiemetic.[4] It is produced and marketed under the trade name Benadryl by McNeil-PPC (a division of Johnson & Johnson) in the U.S., Canada and South Africa (other trade names in other countries: Dimedrol, Daedalon). It is also available as a generic or store brand medication. It is also found in the name-brand products Nytol, Unisom, Tylenol PM, Midol PM and Advil PM, though some Unisom products contain doxylamine instead. It is available as an over-the-counter (OTC) or prescribed HCl injectable. It may also be used for the treatment of extrapyramidal side-effects of many antipsychotics, such as the tremors that haloperidol can cause. In addition, injectable diphenhydramine can be used for life-threatening reactions (anaphylaxis) to allergens such as bee stings, peanuts, or latex, rather than risking the side-effects of epinephrine. It is a member of the ethanolamine class of antihistaminergic agents. An alternative IUPAC name is [2-(diphenylmethoxy)ethyl]dimethylamine.

Diphenhydramine was one of the first known antihistamines, invented in 1943 by Dr. George Rieveschl, a former professor at the University of Cincinnati.[5] In 1946, it became the first prescription antihistamine approved by the U.S. Food and Drug Administration (FDA).[6]

Contents

Medical uses

Diphenhydramine is used to treat a number of conditions including: allergic symptoms and itchiness, the common cold, insomnia, motion sickness, and extrapyramidal symptoms.[7]

It is a first-generation antihistamine drug. Despite being one of the oldest antihistamines on the market, it is more effective than even some of the latest prescription drugs.[8] Consequently, it is frequently used when an allergic reaction requires fast, effective reversal of the often dangerous effects of a massive histamine release.

Diphenhydramine has sedative properties and is widely used in nonprescription sleep aids, with a maximum recommended dose of 50 mg (as the hydrochloride salt) being mandated by the U.S. FDA. In the United Kingdom, Australia, New Zealand, South Africa, and other countries, a 50–100 mg recommended dose is permitted.[citation needed]

Diphenhydramine also has antiemetic properties which make it useful in treating the nausea that occurs in motion sickness. As it causes marked sedation in many individuals, the less sedating drug dimenhydrinate may be preferred for this purpose.

The drug is an ingredient in several products sold as sleep aids, either alone or in combination with other ingredients such as acetaminophen (paracetamol). An example of the latter is Tylenol PM. Examples of products having diphenhydramine as the only active ingredient include Unisom gelcaps (the tablet form contains doxylamine, a different active ingredient), Tylenol Simply Sleep, Nytol, and Sominex (the version sold in the US; that sold in the UK uses promethazine).

There are also topical formulations of diphenhydramine available, including creams, lotions, gels, and sprays. They are used to relieve itching, and have the advantage of causing much less systemic effect (i.e. drowsiness) than oral forms.[citation needed] As diphenhydramine is extensively metabolized by the liver, caution should be exercised when giving the drug to individuals with hepatic impairment.

Adverse effects

Like many other first-generation antihistamines, diphenhydramine can cause strong sedation, due to H1 receptor antagonism. As such, diphenhydramine has also been used as an anxiolytic because of this side-effect. It is also a potent anticholinergic agent, leading to the side-effects of dry mouth and throat, increased heart rate, pupil dilation, urinary retention, constipation, and, at high doses, hallucinations or delirium. Further side-effects include motor impairment (ataxia), flushed skin, blurred vision at nearpoint owing to lack of accommodation (cycloplegia), abnormal sensitivity to bright light (photophobia), difficulty concentrating, short-term memory loss, visual disturbances, irregular breathing, dizziness, irritability, itchy skin, confusion, decreased body temperature (in general, in the hands and/or feet), erectile dysfunction, excitability, and, although it can be used to treat nausea, higher doses may cause vomiting.[9] Some side-effects, such as twitching, may be delayed until the drowsiness begins to cease and the person is in more of an awakening mode. Diphenhydramine also has local anesthetic properties, and has been used for patients allergic to common local anesthetics like lidocaine.[10]

There are several levels of evidence strongly indicating diphenhydramine (similar to chlorpheniramine) can block the delayed rectifier potassium channel and consecutively prolong the QT-interval, leading to cardiac arrhythmias, such as torsade de pointes.[11]

Diphenhydramine is similar in its effects to dimenhydrinate, its 8-chlorotheophylline salt, although the latter is approximately 60% the potency in terms of required dosage and is slightly less sedating.

Some patients have an allergic reaction to diphenhydramine in the form of hives.[12][13]

Since 2002, the US FDA requires special labeling warning against using multiple products that contain diphenhydramine.[14] Diphenhydramine has been shown to build tolerance against its sedation effectiveness very quickly, with placebo-like results after a third day of common dosage.[15]

Paradoxical reactions to diphenhydramine are documented, in particular, among children, and it may cause excitation instead of sedation.[16][17]

Diphenhydramine is on the "Beers list" to avoid in the elderly.[18]

Benadryl Itch Stopping Gel contains additional ingredients, including camphor. It is dangerous when swallowed.[citation needed]

Measurement in body fluids

Diphenhydramine may be quantitated in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest, or assist in a medicolegal death investigation.[citation needed] Blood or plasma diphenhydramine concentrations are usually in a range of 10-150 μg/L in persons taking the drug orally for its antiemetic, antihistaminic or sedative effects, 0.7-2.7 mg/L (700-2700 μg/L) in those arrested for impaired driving, 1–5 mg/L in survivors of acute overdosage and 5–30 mg/L in victims of fatal overdosage.[citation needed] In some jurisdictions, diphenhydramine is often present in postmortem specimens collected during investigation of sudden infant deaths; the drug may play a role in these events.[19][20]

Mechanism of action

Diphenhydramine is a histamine H1 receptor antagonist.[21] By blocking histamine in the capillaries it can reduce the intensity of allergic symptoms. Diphenhydramine crosses the blood-brain barrier(BBB) and antagonizes the H1 receptors centrally. Its effects on central H1 receptors causes drowsiness.[22]

Like several other first-generation antihistamines, diphenhydramine is also a potent competitive antagonist of muscarinic cholinergic receptors, and, as such, at high doses can cause anticholinergic syndrome.[23]

In the 1960s, diphenhydramine was found to inhibit reuptake of the neurotransmitter serotonin. This discovery led to a search for viable antidepressants with similar structures and fewer side-effects, culminating in the invention of fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI).[24][25] A similar search had previously led to the synthesis of the first SSRI, zimelidine, from brompheniramine, also an antihistamine.

Diphenhydramine also acts as a sodium channel blocker, which is responsible for its actions as a local anesthetic.[26]

Chemistry

Diphenhydramine, N,N-dimethyl-(diphenylmethoxy)ethylamine, is synthesized by a simple reaction of benzhydrylbromide and 2-dimethylaminoethanol. Diphenhydramine synthesis.png

Recreational use

Diphenhydramine acts as an analgesia potentiator with morphine in rats.[27] It is used recreationally as a deliriant, a depressant,[citation needed] or a potentiator of alcohol,[citation needed] DXM[28][citation needed] and some opiates.[29] CNS effects occur within the limbic system and hippocampus, causing confusion and temporary amnesia.[citation needed]

Toxicology also manifests in the autonomic nervous system, causing urinary retention, pupil dilation, tachycardia, irregular urination, and dry skin and mucous membranes.[citation needed] Severe restlessness or akathesia can also be a side effect that is made worse by increased levels of diphenhydramine.[30] Considerable overdosage can lead to cardiac arrest, serious ventricular dysrhythmias, coma, and death.[citation needed]Such a side-effect profile is commonly thought to give ethanolamine-class antihistamines a relatively low abuse liability. The specific antidote for diphenhydramine poisoning (similar to that of Datura or Atropa belladonna poisoning) is physostigmine, usually given intravenously in a hospital.[citation needed]

Diphenhydramine is among the prohibited and controlled substances in the Republic of Zambia.[31] Travelers are advised not to bring this drug into the country. Several Americans have been detained by the Zambian Drug Enforcement Commission for possession of Benadryl and other over-the-counter medications containing diphenhydramine.[32]

See also

References

Notes

  1. ^ "Showing Diphenhydramine (DB01075)". DrugBank. http://www.drugbank.ca/drugs/DB01075. Retrieved 5 September 2009. 
  2. ^ Sweetman, Sean C., ed (2009). "Antihistamines". Martindale: The complete drug reference (36th ed.). London: Pharmaceutical Press. pp. 577–8. ISBN 978-0-85369-840-1. 
  3. ^ Garnett, WR (1986). "Diphenhydramine". Am Pharm (NS26(2)): 35–40. 
  4. ^ Diphenhydramine Hydrochloride (2005) http://www.assistpainrelief.com/dyn/305/Diphenhydramine-Hydrochloride.html AssistPainRelief.
  5. ^ Hevesi D (2007-09-29). "George Rieveschl, 91, Allergy Reliever, Dies". The New York Times. http://www.nytimes.com/2007/09/29/business/29rieveschl.html?ref=health. Retrieved 2008-10-14. 
  6. ^ Ritchie J (2007-09-24). "UC prof, Benadryl inventor dies". Business Courier of Cincinnati. http://www.bizjournals.com/cincinnati/stories/2007/09/24/daily52.html. Retrieved 2008-10-14. 
  7. ^ "diphenhydramine-hydrochloride". The American Society of Health-System Pharmacists. http://www.drugs.com/monograph/diphenhydramine-hydrochloride.html. Retrieved 3 April 2011. 
  8. ^ Raphael GD, Angello JT, Wu MM, Druce HM (April 2006). "Efficacy of diphenhydramine vs desloratadine and placebo in patients with moderate-to-severe seasonal allergic rhinitis". Annals of allergy, asthma & immunology 96 (4): 606–14. doi:10.1016/S1081-1206(10)63557-0. PMID 16680933. 
  9. ^ "Diphenhydramine Side Effects". Drugs.com. http://www.drugs.com/sfx/diphenhydramine-side-effects.html. Retrieved 2009-04-06. 
  10. ^ Smith DW, Peterson MR, DeBerard SC (August 1999). "Local anesthesia. Topical application, local infiltration, and field block". Postgraduate medicine 106 (2): 57–60, 64–6. doi:10.3810/pgm.1999.08.650. PMID 10456039. 
  11. ^ (Nia et al. in Eur J Clin Pharmacol. 2010 Nov;66(11):1173-5. Epub 2010 Jul 31 Torsades de pointes tachycardia induced by common cold compound medication containing chlorpheniramine)
  12. ^ Heine A (November 1996). "Diphenhydramine: a forgotten allergen?". Contact dermatitis 35 (5): 311–2. doi:10.1111/j.1600-0536.1996.tb02402.x. PMID 9007386. 
  13. ^ Coskey RJ (February 1983). "Contact dermatitis caused by diphenhydramine hydrochloride". Journal of the American Academy of Dermatology 8 (2): 204–6. doi:10.1016/S0190-9622(83)70024-1. PMID 6219138. 
  14. ^ Food and Drug Administration, HHS (2002). "Labeling of Diphenhydramine-Containing Drug Products for Over-the-Counter Human Use". Federal Register 67 (235): 72555–9. PMID 12474879. http://www.fda.gov/OHRMS/DOCKETS/98fr/120602a.htm. Retrieved 2008-10-14. 
  15. ^ Richardson, GS; Roehrs TA; Rosenthal L; Koshorek G; Roth T. (October 2002). "Tolerance to daytime sedative effects of H1 antihistamines.". Journal of Clinical Psychopharmacology 22 (5): 511–5. doi:10.1097/00004714-200210000-00012. PMID 12352276. 
  16. ^ http://www.astm.org/JOURNALS/FORENSIC/PAGES/JFS2002121_482.htm
  17. ^ de Leon J, Nikoloff DM (February 2008). "Paradoxical excitation on diphenhydramine may be associated with being a CYP2D6 ultrarapid metabolizer: three case reports". CNS Spectr 13 (2): 133–5. PMID 18227744. 
  18. ^ NCQA’s HEDIS Measure: Use of High Risk Medications in the Elderly
  19. ^ Marinetti, L; Lehman, L; Casto, B; Harshbarger, K; Kubiczek, P; Davis, J (2005). "Over-the-counter cold medications-postmortem findings in infants and the relationship to cause of death.". Journal of analytical toxicology 29 (7): 738–43. PMID 16419411. 
  20. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 489-492.
  21. ^ Yamashiro, K; Kiryu, J; Tsujikawa, A; Nonaka, A; Honjo, M; Tanihara, H; Nishiwaki, H; Honda, Y et al. (2001). "Suppressive effects of histamine H1 receptor antagonist diphenhydramine on the leukocyte infiltration during endotoxin-induced uveitis". Experimental eye research 73 (1): 69–80. doi:10.1006/exer.2001.1008. PMID 11428864. 
  22. ^ Reiner PB, Kamondi A (April 1994). "Mechanisms of antihistamine-induced sedation in the human brain: H1 receptor activation reduces a background leakage potassium current". Neuroscience 59 (3): 579–88. doi:10.1016/0306-4522(94)90178-3. PMID 8008209. 
  23. ^ http://emedicine.medscape.com/article/812828-overview.
  24. ^ Domino, Edward F. History of Modern Psychopharmacology: A Personal View With an Emphasis on Antidepressants. Psychosomatic Medicine 61:591-598 (1999).
  25. ^ http://meeting.chestjournal.org/cgi/content/abstract/134/4/c4002
  26. ^ Kim YS, Shin YK, Lee C, Song J (October 2000). "Block of sodium currents in rat dorsal root ganglion neurons by diphenhydramine". Brain Research 881 (2): 190–8. doi:10.1016/S0006-8993(00)02860-2. PMID 11036158. http://linkinghub.elsevier.com/retrieve/pii/S0006899300028602. 
  27. ^ Carr KD, Hiller JM, Simon EJ (February 1985). "Diphenhydramine potentiates narcotic but not endogenous opioid analgesia". Neuropeptides 5 (4–6): 411–4. doi:10.1016/0143-4179(85)90041-1. PMID 2860599. http://linkinghub.elsevier.com/retrieve/pii/0143-4179(85)90041-1. [dead link]
  28. ^ "DXM - Drugs Forum." Drugs-forum. Web. 11 Dec. 2010. <http://www.drugs-forum.com/forum/showwiki.php?title=DXM>.
  29. ^ Sandor, Ivo. "Opiate Potentiation and Side-effects." Opioids : Past, Present and Future. 30 July 2000. Web. 11 Dec. 2010. <http://www.opioids.com/opiates/index.html>.
  30. ^ http://www.medicalnewstoday.com/releases/129785.php
  31. ^ "The Drug Enforcement Commission ZAMBIA: LIST OF PROHIBITED AND CONTROLLED DRUGS ACCORDING TO CHAPTER 96 OF THE LAWS OF ZAMBIA". http://www.deczambia.gov.zm/listofdrugs.html. 
  32. ^ "travel.state.gov: Zambia". http://travel.state.gov/travel/cis_pa_tw/cis/cis_1062.html. 

Sources

  • J.A. Lieberman, History of the use of antidepressants in primary care. Primary Care Companion, J. Clinical Psychiatry, 2003; 5 (supplement 7).

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Look at other dictionaries:

  • Diphenhydramine — Général No CAS …   Wikipédia en Français

  • Diphénhydramine — Général Nom IUPAC 2 (diphénylméthoxy) N,N diméthyléthanamine No CAS …   Wikipédia en Français

  • diphenhydramine — /duy fen huy dreuh meen /, n. Pharm. a white, crystalline, antihistaminic compound, C17H21NO, used orally, topically, and parenterally, esp. for allergies. [1945 50; DIPHEN(YL) + HYDR 2 + AMINE] * * * ▪ drug       synthetic drug used in the… …   Universalium

  • diphenhydramine hydrochloride — An H2 antihistaminic with anticholinergic and sedative properties. * * * [USP] the hydrochloride salt of diphenhydramine, used for the symptomatic treatment of allergic symptoms, for the treatment of anaphylaxis, parkinsonism or drug induced… …   Medical dictionary

  • diphenhydramine citrate — [USP] the citrate salt of diphenhydramine, used as a sedative and hypnotic; administered orally …   Medical dictionary

  • diphenhydramine — noun Date: 1948 an antihistamine C17H21NO used especially in the form of its hydrochloride …   New Collegiate Dictionary

  • diphenhydramine — noun An antihistamine and sedative drug that blocks the effect of histamine at H1 receptor sites, reducing smooth muscle contraction …   Wiktionary

  • diphenhydramine — di·phen·hy·dra·mine .dī .fen hī drə .mēn n an antihistamine used esp. in the form of its hydrochloride C17H21NO·HCl to treat allergy symptoms and motion sickness and to induce sleep see BENADRYL * * * n. an antihistamine with sedative properties… …   Medical dictionary

  • diphenhydramine — n. chemical compound used as an anti allergy medication …   English contemporary dictionary

  • diphenhydramine — [ˌdʌɪfɛn hʌɪdrəmi:n] noun Medicine an antihistamine compound used for the symptomatic relief of allergies …   English new terms dictionary

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